Primary Active Transport of Sodium

Primary active transport accounts for most Na⁺ reabsorption from the tubular filtrate and occurs in all tubules except the descending loop of Henle.¹ On the nonluminal side of the tubular epithelial cell (Figure 22-1), the sodium-potassium-adenosine triphosphatase (Na⁺-K⁺-ATPase) pump actively transports Na⁺ ions out of the cell, into the interstitial fluid, and ultimately into the peritubular capillary blood. The membrane protein forming this pump hydrolyzes ATP molecules to generate the energy necessary to actively transport Na⁺ ions out of the cell. K⁺ ions are simultaneously transported into the cell from the interstitial fluid, but more Na⁺ ions are pumped out of the cell than K⁺ ions are pumped in. This process keeps Na⁺ concentration in the tubule cell very low and creates a negatively charged intracellular environment.

Because [Na⁺] is comparatively much higher in the tubular filtrate, and Na⁺ is a positively charged ion, both chemical diffusion and electrostatic forces favor its movement from the tubular lumen into the cell, down its concentration and electrostatic gradients.¹ Specialized sodium-carrier proteins in the luminal membrane of the tubule cell facilitate this process by binding with Na⁺ ions and releasing them inside of the tubule cell. Cl⁻ ions passively follow Na⁺ ions, which maintains the filtrate’s electrical neutrality. That is, the transport of the positively charged Na⁺ ion out of the filtrate into the tubular cell leaves the tubular lumen negatively charged with respect to the extracellular fluid and the blood; this electrostatic gradient causes Cl⁻ (the most abundant anion in the filtrate) to diffuse passively through paracellular pathways (between the tubule cells) into the interstitial space and ultimately into the capillary blood.¹ Cl⁻ diffusion also occurs because of a concentration gradient; that is, Na⁺ transport out of the filtrate creates an osmotic gradient for water reabsorption from the tubular lumen, which concentrates Cl⁻ ions in the filtrate. Cl⁻ thus passively diffuses out of the filtrate in response to both electrostatic and chemical diffusion forces.¹

The brush border on the luminal side of the epithelial cell provides an extensive surface area for Na⁺ transport. Sodium-carrier proteins in these membranes are also important in secondary active reabsorption, or cotransport.

Secondary Active Secretion of Hydrogen and Potassium

Reabsorption of Na⁺ by way of the active secretion of H⁺ and K⁺ ions is a more complex process. For H⁺ secretion (Figure 22-2), the process proceeds in the following manner: First, carbon dioxide (CO₂) from the peritubular capillary blood diffuses into the tubular cells, where it reacts with water (in the presence of carbonic anhydrase) and forms H⁺ ions. The H⁺ ion in the tubule cell and Na⁺ ion in the filtrate simultaneously combine with opposite ends of a protein-carrier molecule in the luminal border of the cell membrane. Na⁺ diffusion into the cell, down its concentration and electrostatic gradients (described previously), provides the energy for H⁺ transport into the filtrate (see Figure 22-2). This process is called countertransport because the transported ions move in opposite directions. Figure 22-2 shows that the < ?xml:namespace prefix = "mml" />HCO3− ion generated by the reaction between CO₂ and water accompanies Na⁺ transport out of the cell and into the peritubular capillaries. In this way, Na⁺ reabsorption from the filtrate occurs without Cl⁻ reabsorption. A similar countertransport mechanism is involved in the secondary active secretion of K⁺ into the tubules in exchange for Na⁺ (Figure 22-3). This mechanism of potassium secretion is more likely to occur in the presence of alkalemia when H⁺ is scarce; this is the reason alkalemia tends to cause K⁺ depletion (hypokalemia).

Normally, a relatively small amount of the total Na⁺ reabsorption occurs by way of active H⁺ and K⁺ secretion mechanisms. In H⁺ and K⁺ secretion, HCO₃⁻ ion rather than Cl⁻ ion is reabsorbed into the blood with Na⁺. Cl⁻ ion shortage (as may occur with diuretic therapy) increases the demand for H⁺ and K⁺ secretion as a mechanism for reabsorbing sodium.

Secondary Active Transport of Chloride

In most of the tubular segments, Cl⁻ ions are reabsorbed with Na⁺ ions by passive diffusion as described earlier. In the thick segment of the loop of Henle, Cl⁻ ions are transported in a secondary active transport process also known as cotransport. In this mechanism, the same carrier protein referred to previously that combines with Na⁺ in the luminal tubular membrane simultaneously combines with Cl⁻. As Na⁺ diffuses down its electrochemical gradient into the tubule cell, it pulls Cl⁻ with it. This secondary active transport of Cl⁻ requires no ATP energy source; it simply uses the force of the Na⁺ ions’ “downhill” diffusion into the cell to energize the process. In addition to Cl⁻, a significant amount of K⁺ is reabsorbed with Na⁺ through the same mechanism; for each Na⁺ ion, two Cl⁻ ions and one K⁺ ion are cotransported by a membrane carrier protein known as the 1 sodium, 2 chloride, 1 potassium cotransporter.¹

Potassium Reabsorption

About 65% of K⁺ in the filtrate is reabsorbed into the blood by cotransport with Na⁺ and Cl⁻ in the proximal tubules (by way of the 1 sodium, 2 chloride, 1 potassium cotransporter).¹ Anything that blocks Na⁺ reabsorption, such as a loop diuretic, impairs K⁺ (and Cl⁻) reabsorption; overuse of loop diuretics can cause hypokalemia and hypochloremia. Approximately another 25% of the filtrate’s K⁺ is reabsorbed by the same cotransport mechanism in the ascending limb of the loop of Henle. The small amount of K⁺ remaining in the filtrate after it leaves the loop of Henle is almost completely reabsorbed by the distal tubule and cortical segments of the collecting ducts. However, the kidneys must excrete a quantity of K⁺ in the urine at least equal to the daily K⁺ intake to avoid hyperkalemia.

Potassium Excretion

The late distal tubule and cortical portion of the collecting duct secrete K⁺ into the tubular filtrate. This secretion occurs in the following way: First, the Na⁺,K⁺-ATPase pump in the nonluminal cell membrane pumps Na⁺ out of the cell and into the interstitial fluid, while it pumps K⁺ into the cell, increasing its intracellular concentration. Second, because the luminal border of the late distal tubule and cortical collecting duct is permeable to K⁺ (unlike tubular cells elsewhere in the nephron), K⁺ diffuses into the tubular filtrate. Thus, for the K⁺ secretion mechanism to work, Na⁺ in the filtrate must continually diffuse into the cell and be exchanged for K⁺ at the nonluminal cell membrane.

Control of Potassium Excretion

Because it greatly influences cardiac impulse conduction (see Chapter 18 and nervous system function, extracellular fluid [K⁺] regulation is especially important. K⁺ ion excretion is controlled by (1) extracellular fluid [K⁺] and (2) aldosterone secretion by the adrenal gland cortex.²

A rising extracellular [K⁺] directly stimulates tubular K⁺ secretion, especially when [K⁺] is already above the normal range. It does so by stimulating the Na⁺,K⁺-ATPase pump, increasing K⁺ uptake through the nonluminal tubule cell membrane. Conversely, low extracellular [K⁺] depresses the rate of K⁺ secretion. Extracellular fluid [K⁺] also directly affects the rate of aldosterone secretion by the adrenal cortex.¹ Aldosterone also activates the Na⁺,K⁺-ATPase pump, pumping more K⁺ into the tubular cell as it pumps more Na⁺ out of the cell. A functioning aldosterone system is extremely important in regulating extracellular [K⁺]. Diseases that abnormally increase aldosterone secretion, such as primary aldosteronism, greatly increase K⁺ secretion into the filtrate, causing severe hypokalemia. Conversely, diseases that destroy the adrenal glands, such as Addison’s disease, stop aldosterone production and produce severe hyperkalemia.

Tubular Hydrogen Ion Secretion

All parts of the nephron’s tubular system actively secrete H⁺ except the thin segments of the loop of Henle. About 95% of H⁺ secretion occurs via secondary active transport; the remaining 5% occurs via primary active transport.¹

Secondary active secretion of H⁺ occurs mainly in the proximal tubules, loop of Henle, and early distal tubules. This process is the same as that described for the Na⁺ reabsorption mechanism (see Figure 22-2). First, CO₂ in the peritubular blood plasma freely diffuses into the tubular cell, where it reacts instantly with water under the influence of carbonic anhydrase. As a result, carbonic acid forms and dissociates into HCO3− and H⁺ ions. The H⁺ ions are secreted into the tubular filtrate by the Na⁺-H⁺ countertransport mechanism described previously (see Figure 22-2). The luminal brush border of the tubule cell is impermeable to HCO3−; therefore HCO3− cannot follow H⁺, and intracellular [HCO3−] increases. In this way, a concentration gradient for HCO3− diffusion is formed, and it diffuses out of the cell along with newly reabsorbed Na⁺ into the interstitial fluid and peritubular capillary blood. Generally, for every H⁺ ion secreted, one HCO3− ion enters the blood.

Primary active secretion accounts for a small amount of H⁺ secretion, occurring in the late distal tubule and the entire length of the collecting duct. In this process, a specific transport protein in the tubule cell luminal membrane, hydrogen-transporting ATPase, pumps the H⁺ formed by the reaction between CO₂ and water into the filtrate. The only difference between this process and secondary active secretion is that H⁺ ions are transported across the luminal membrane by an active hydrogen pump instead of by countertransport with Na⁺ ions. Although this mechanism accounts for only about 5% of the total H⁺ secreted, it is much more powerful than the secondary active secretion mechanism. Primary active transport can concentrate H⁺ ions in the filtrate 900-fold compared with a maximum of about 3-fold to 4-fold for the secondary process.¹ This extreme H⁺ ion concentrating ability can reduce urine pH to a maximum of about 4.5. All tubular H⁺ secretion stops below this pH level.¹

Hydrogen Ion Secretion and Bicarbonate Ion Reabsorption

The H⁺ ion secreted into the filtrate immediately reacts with the HCO3− ion (see Figure 22-2). (Remember that numerous HCO3− ions are filtered out of the blood at the glomerulus.) When the HCO3− ion buffers the secreted H⁺ ion, H₂CO₃ and ultimately CO₂ and water are formed. All cell membranes are freely permeable to CO₂; CO₂ immediately diffuses into the tubular cell where it instantly reacts with water under the influence of carbonic anhydrase. Again, the CO₂ hydrolysis reaction produces a HCO3− ion; the intracellular concentration of HCO3− thus increases, and it diffuses into the interstitial fluid. In this way, the filtrate’s HCO3− ions are “reabsorbed” into the blood, although the reabsorbed HCO3− ion is not the same ion that was in the filtrate.

Normally, H⁺ secretion slightly exceeds the rate of HCO3− filtration at the glomerulus. This means that the titration of HCO3− against H⁺ in the tubular filtrate is incomplete, leaving a slight excess of H⁺. Thus, the excreted urine is usually slightly acidic.¹

Phosphate Buffers

Phosphate buffers in the tubular filtrate include HPO4−2 and H2PO4−. Because these buffer anions are poorly reabsorbed from the filtrate, they become concentrated and powerful as water is reabsorbed. The phosphate buffer system’s pK_a is 6.8, a pH level close to that of the tubular filtrate.¹ This means the phosphate buffer system operates in its most effective range in the tubular filtrate (see Chapter 10). The function of the phosphate buffer system is illustrated in Figure 22-6.

Ammonia Buffer System

The ammonia buffer system consists of the ammonia molecule (NH₃) and ammonium ion (NH4+). Most of the tubular epithelium synthesizes NH₃, which diffuses into the filtrate (Figure 22-7). The NH₃ molecule buffers the H⁺ ion in the filtrate, forming NH₄⁺. Every time this process occurs, the filtrate NH₃ concentration decreases, causing more NH₃ to diffuse out of the tubule cell, which stimulates more NH₃ synthesis. In this way, the amount of free H⁺ in the filtrate controls the rate of NH₃ synthesis.

The NH₄⁺ ion must be excreted with a negative ion in the filtrate to maintain electroneutrality. The most abundant filtrate anion, Cl⁻, tends to be excreted with NH₄⁺ as the NH₄Cl molecule (ammonium chloride). Ammonium chloride is an extremely weak acid and does not lower the filtrate pH much. Without the ammonia secretion mechanism, the excess H⁺ ions in the filtrate would react with Cl⁻ ions, forming the strong acid, HCl. Filtrate pH would then quickly decrease below 4.5 and stop the tubule cells from secreting more H⁺ ions.

People with chronic acidosis (e.g., patients with chronic obstructive pulmonary disease [COPD] and chronic CO₂ retention) produce large amounts of NH₃ in their kidneys to buffer excess H⁺ ions. Because the resulting NH₄⁺ ions require an equally large amount of Cl⁻ excretion, these patients tend to become hypochloremic. As discussed previously, hypochloremia interferes with Na⁺ reabsorption because the main mechanism for reabsorbing Na⁺ involves simultaneous Cl⁻ reabsorption. Therefore, to reabsorb Na⁺ (always a first priority), people with chronic acidosis rely more on the secondary H⁺ and K⁺ secretion mechanisms. This reliance tends to deplete the body’s H⁺ and K⁺ stores, producing hypokalemia and a relative alkalemia; that is, even though blood pH may be in the normal range in this situation, it is on the alkalotic side of normal.

Alkalosis Caused by Hypokalemia

Similarly, a state of hypokalemia also can cause alkalosis. For example, diuretic therapy or lack of dietary K⁺ intake may cause hypokalemia. The tubules must then secrete inappropriately large amounts of H⁺ ions to reabsorb Na⁺ via the countertransport mechanism (see Figure 22-2), which normally accounts for a relatively small percentage of Na⁺ reabsorption. Consequently, alkalosis occurs. Hypokalemic alkalosis is compounded by a coexisting state of dehydration.³ Dehydration produces a profound stimulus for Na⁺ reabsorption, which (coupled with hypokalemia) intensifies the kidney’s need to secrete H⁺. Overuse of diuretic drugs can lead to such a condition.

Acidosis Caused by Hyperkalemia

Conversely, hyperkalemia has the opposite effect. The high plasma [K⁺] in hyperkalemia stimulates increased K⁺ secretion into the filtrate, as described earlier. This increased filtrate K⁺ competes with H⁺ for the filtrate’s buffer anions. As a result, the tubules secrete inappropriately low amounts of H⁺, leading to an increased plasma [H⁺] and acidemia.

Intracellular Mechanisms Affecting Plasma Hydrogen Ion Concentration and Potassium Ion Concentration

The relationship of [K⁺] and plasma pH has a further explanation at the cellular level in the body.⁴ These interrelationships are illustrated in red blood cells in Figure 22-8 (the same relationships are also present in all of the body’s cells). Plasma hypokalemia creates a concentration gradient that favors intracellular K⁺ diffusion out of the cell (Figure 22-8, A). The resulting intracellular negativity causes a net movement of plasma H⁺ into the cell. The reduction in plasma [H⁺] produces alkalemia. Conversely, in alkalemia (Figure 22-8, B), intracellular H⁺ ions diffuse out of the cell in response to a H⁺ ion concentration gradient, and plasma K⁺ diffuses into the cell. The movement of K⁺ into the cell causes hypokalemia.

Similarly, in acidemia (Figure 22-8, C), the plentiful plasma H⁺ diffuses into the cell, and K⁺ diffuses out of the cell, producing hyperkalemia. Conversely, hyperkalemia causes K⁺ to move into the cell and H⁺ to move out of the cell, causing acidemia (Figure 22-8, D).

Because of these intracellular-extracellular K⁺ shifts, the plasma [K⁺] on a clinical laboratory report must be interpreted carefully. In the examples in Figure 22-8, total body stores of K⁺ do not change; K⁺ merely shifts between fluid compartments. However, consider the acidotic condition in Figure 22-8, C, in which plasma [K⁺] increases. In response to the increasing [K⁺], the kidneys excrete more K⁺, causing more K⁺ to diffuse out of the cells into the plasma. Thus, plasma [K⁺] may be normal or high, but total body K⁺ stores may actually be depleted. Similarly, low [K⁺] in alkalemia (see Figure 22-8, B) does not always mean the body’s K⁺ stores are depleted.

Reduced Renal Blood Flow

If renal blood flow remains greater than 20% to 25% of normal, kidney cell ischemia is generally not severe enough to cause cell death.¹ Blood flow below this level can cause hypoxic cell damage and death (renal infarction).

Intrarenal Failure

Intrarenal failure includes conditions that injure the glomerular capillaries, the tubular epithelium, and the renal interstitium. Acute glomerulonephritis is an example of a disease that is usually caused by an abnormal immune reaction in which the body develops antibodies to group A beta streptococci microorganisms.¹ Renal manifestations of the disease usually follow streptococcal infections elsewhere in the body, such as the throat or skin. The streptococcal antigen-antibody complex lodges in the basement membrane of the glomerulus; this causes a general inflammatory glomerular reaction, blocking the glomerular capillaries or making them excessively permeable. High glomerular permeability allows plasma proteins and red blood cells to leak into the filtrate. As a result, plasma oncotic pressure decreases, which accounts for pleural effusions in the chest that often accompany acute glomerulonephritis.⁵ (That is, plasma oncotic pressure may become so low that it can no longer keep fluids from leaking out of the vascular space into the pleural cavity.) In severe instances, total renal shutdown occurs. The acute inflammation usually disappears in a few weeks to a few months.¹

Another form of intrarenal failure is tubular necrosis. Certain poisons and severe renal ischemia can cause tubular necrosis (death of tubular epithelial cells).¹ Renal poisons include carbon tetrachloride and mercury compounds. In addition, tetracycline antibiotics and some anticancer drugs are toxic to the nephron.¹ Dead epithelial cells slough away from their attachments and plug the tubules, preventing the normal flow of filtrate. Severe renal ischemia, usually caused by acute cardiovascular failure, also can kill tubular epithelial cells and plug the tubular lumen.

Postrenal Failure

Postrenal failure occurs when obstructions to renal outflow occur. If this involves only one kidney, the other kidney can usually maintain normal fluid and electrolyte balance. If obstruction affects both kidneys and persists for several days, it can lead to irreversible kidney damage.¹ Causes of obstruction include kidney stones and blood clots of the ureters, which also may block the bladder opening or the urethra.¹

Blood Transfusion Reactions

Severe immune reactions to blood transfusion can cause acute renal failure. Transfusion reactions are characterized by the destruction of many red blood cells, releasing hemoglobin into the plasma. The hemoglobin molecule is small enough to pass through the glomerular membrane but may not be adequately reabsorbed by the proximal tubules. Excess hemoglobin in the filtrate precipitates and blocks the tubules.¹

All of the foregoing forms of acute renal failure prevent the normal flow of filtrate through the tubules. Consequently, the kidneys retain sodium and fluid because they cannot excrete these substances. As a result, body tissues become edematous, and blood pressure increases.¹

Physiological Effects of Chronic Renal Failure

Generally, the kidneys can maintain adequate function with only one third of the normal number of nephrons. Further reduction in functioning nephrons increases the body’s retention of waste products, especially urea and creatinine. The tubular filtrate load of solutes in the remaining functional nephrons increases greatly, exceeding the kidney’s reabsorption capacity. Consequently, the solutes remaining in the filtrate act as osmotic diuretics, increasing each nephron’s filtrate flow and urine output. Despite significant renal impairment, total urine output often paradoxically increases.¹ In other words, the increase in each nephron’s urine output outweighs the effect of decreased nephron numbers. The high flow rate of filtrate through the remaining functional tubules impairs the kidney’s urine-concentrating ability. Flow is too rapid through the collecting ducts for adequate water reabsorption to occur. Consequently, the kidneys excrete dilute urine, manifested by a decrease in the urine’s specific gravity.¹

If a person with complete renal shutdown continues to ingest food and water, extracellular concentrations of nitrogenous waste products, sodium, potassium, and fixed acids rapidly increase. The most important effects of retaining these substances are the following:¹ (1) general edema secondary to salt and water retention; (2) metabolic acidosis caused by the kidney’s failure to excrete fixed acids; (3) high blood concentrations of nitrogenous compounds such as urea, creatinine, and uric acid, which are end products of protein breakdown; and (4) increased blood concentration of phenols, sulfates, phosphates, and potassium. This condition is called uremia because of the high urea concentrations in all body fluids. After about one week of renal failure, patients develop a confused mental state that may progress to a condition known as uremic coma. Acidosis, which depresses the central nervous system, is apparently responsible for the coma.¹